Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The past 15 years have been witness to a remarkable growth in knowledge regarding the modulation of "sympathetic traffic" to neuroeffector organs, including vascular tissue. The release of norepinephrine from peripheral sympathetic neurons is now known to be under both negative and positive feedback control. Norepinephrine, when released from peripheral neurons, acts on presynaptic alpha 2-receptors to inhibit further neurotransmission. Vascular postsynaptic alpha 2-receptors, sensitive to circulating catecholamines, subserve vasoconstriction. The antihypertensive agents clonidine, guanabenz and guanfacin likely reduce blood pressure by acting centrally on alpha 2 postsynaptic neurons to limit sympathetic transmission to blood vessels. Clonidine can produce venoconstriction and thereby improve orthostatic hypotension by activating venous alpha 2-receptors. Additional presynaptic dopaminergic receptors (DA2), muscarinic receptors (acetylcholine), opioid receptors, prostaglandin receptors, adenosine receptors (A1) and histamine (H2) receptors are present on sympathetic nerve membranes and, when engaged with the appropriate ligand, can limit the exocytotic process. Gamma-aminobutyric acid and serotonin demonstrate similar roles in reducing sympathetic nerve activity. In contrast to these inhibitory presynaptic mechanisms, facilitation of norepinephrine release appears to occur by way of neuronal angiotensin II receptor activation and perhaps through stimulation of sympathetic nerve membrane beta 2-receptors. An appreciation of these inhibitory and facilitator mechanisms is useful in the treatment of a variety of clinical conditions, including hypertension, heart failure, orthostatic hypotension, septic shock and a number of common withdrawal syndromes.
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PMID:Modulation of peripheral sympathetic nerve transmission. 283 2

One characteristic of heart failure (HF) is increased sympathetic activation. The paraventricular nucleus (PVN) of the hypothalamus (involved in control of sympathetic outflow) has been shown to have increased neuronal activation during HF. This study examined the influence of endogenous GABA input (inhibitory in nature) into the PVN on renal sympathetic nerve discharge (RSND), arterial blood pressure (BP), and heart rate (HR) in rats with HF induced by coronary artery ligation. In alpha-chloralose- and urethane-anesthetized rats, microinjection of bicuculline (a GABA antagonist) into the PVN produced a dose-dependent increase in RSND, BP, and HR in both sham-operated control and HF rats. Bicuculline attenuated the increase in RSND and BP in HF rats compared with control rats. Alternatively, microinjection of the GABA agonist muscimol produced a dose-dependent decrease in RSND, BP, and HR in both control and HF rats. Muscimol was also less effective in decreasing RSND, BP, and HR in HF rats than in control rats. These results suggest that endogenous GABA-mediated input into the PVN of rats with HF is less effective in suppressing RSND and BP compared with control rats. This is partly due to the post-release actions of GABA, possibly caused by altered function of post-synaptic GABA receptors in the PVN of rats with HF. Reduced GABA-mediated inhibition in the PVN may contribute to increased sympathetic outflow, which is commonly observed during HF.
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PMID:Reduced endogenous GABA-mediated inhibition in the PVN on renal nerve discharge in rats with heart failure. 1189 4

The exact mechanisms by which NO mediates its neuromodulatory effects within the central control of cardiovascular functions are still unclear. Both excitatory and inhibitory actions of NO in different regions of the brainstem have been reported, and that it could be caused by direct actions of NO on neurones and/or by NO-mediated changes in local cerebral blood flow. Microinjection studies suggest that direct modulation of neuronal activity by NO through cyclic 3'-5' guanosine monophosphate (cGMP)-dependent mechanisms predominates. In contrast, endogenous NO produces. only minor changes in local cerebral blood flow, and potentiation of NO-dependent vasodilation with an inhibitor of phosphodiesterase V (PDE5i) has no significant effect on sympathetic activity. Activation of the NO-system in the lower brain stem modulates various central and reflex-activated neuronal pathways. To a large extent, this appears to be mediated by NO-induced GABA- and glutamate-release within the ventrolateral medulla (VLM) and the nucleus of the solitary tract (NTS). In addition, NO has been shown to reduce local generation of angiotensin II (AII) in all areas. Recent studies suggest that the NO-mediated modulation of autonomic function is severely impaired in cardiovascular diseases. Possibly in conjunction with AII, which triggers and promotes superoxide radical generation, chronic oxidative stress (COS) could act as a key mediator of this process. Evidence supporting this hypothesis comes from studies on pigs that were chronically treated with organic nitrates to pharmacologically induce COS. In these animals, microinjection of superoxide dismutase into the rostral VLM (RVLM) diminished sympathetic activity by up to 70%, whereas peroxynitrite, a key mediator of NO-related oxidative stress, had excitotoxic effects. Antagonism of neuronal COS may therefore represent a novel approach to counteract neurohumoral activation in diseases such hypertension, obesity and heart failure.
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PMID:Mechanisms of action of nitric oxide in the brain stem: role of oxidative stress. 1214 34

Heart failure and hypertension are associated with increases in angiotensin II (ANG II) activity. One brain area where ANG II effects may be particularly important in these situations is the nucleus of the solitary tract (NTS). Located in the dorsomedial medulla, the NTS is the termination site of baroreceptor afferents and is essential for mediating the baroreflex. In hypertensive animals the baroreflex is impaired; this may be reversed by antagonizing ANG II AT1 receptors in the NTS. Recently, we showed that the baroreflex depressant action of ANG II in the NTS is mediated by activation of endothelial nitric oxide synthase (eNOS) and enhanced release of GABA. Using conventional pharmacological tools and a range of adenoviral-mediated expression of dominant negative proteins, we have determined the intracellular pathway(s) in the NTS by which ANG II activates eNOS. Our data indicate that ANG II acting in the NTS depresses the baroreflex via a Gq protein-mediated activation of phospholipase C, which through 1,4,5-inositol triphosphate causes release of calcium from the IP3-sensitive intracellular stores and calcium-calmodulin formation. In contrast, multiple site disruption of a pathway leading to eNOS activation via the serine/threonine kinase Akt was ineffective
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PMID:Genetic and pharmacological dissection of pathways involved in the angiotensin II-mediated depression of baroreflex function. 1237 82

It is now well accepted that the sympathetic nervous system responds to specific afferent stimuli in a unique non-uniform fashion. The means by which the brain transforms the signals from a single type of receptor into an appropriate differential sympathetic output is discussed in this brief review. The detection of and response to venous filling are used for illustration. An expansion of blood volume has been shown in a number of species to increase heart rate reflexly via sympathetic nerves and this effect is primarily an action of volume receptors at the venous-atrial junctions of the heart. Stimulation of these volume receptors also leads to an inhibition of renal sympathetic nerve activity. Thus the reflex response to an increase in plasma volume consists of a distinctive unique pattern of sympathetic activity to maintain fluid balance. This reflex is dependent on neurones in the paraventricular nucleus (PVN). Neurones in the PVN show early gene activation on stimulation of atrial receptors, and a similar differential pattern of cardiac sympathetic excitation and renal inhibition can be evoked by activating PVN neurones. Cardiac atrial afferents selectively cause a PVN GABA neurone-induced inhibition within the PVN of PVN spinally projecting vasopressin-containing neurones that project to renal sympathetic neurones. A lesion of these spinally projecting neurones abolishes the reflex. With regard to the cardiac sympathetics, there is a population of PVN spinally projecting neurones that selectively increase heart rate by the release of oxytocin, a peptide pathway that has no action on renal sympathetic outflow. In heart failure the atrial reflex becomes blunted, and evidence is emerging that there is a downregulation of nitric oxide synthesis and reduced GABA activity in the PVN. How this might give rise to increased sympathetic activity associated with heart failure is briefly discussed.
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PMID:A role for the paraventricular nucleus of the hypothalamus in the autonomic control of heart and kidney. 1560 10

1. The long-term level of arterial pressure is dependent on the relationship between arterial pressure and the urinary output of salt and water, which, in turn, is affected by a number of factors, including renal sympathetic nerve activity (RSNA). In the present brief review, we consider the mechanisms within the brain that can influence RSNA, focusing particularly on hypothalamic mechanisms. 2. The paraventricular nucleus (PVN) in the hypothalamus has major direct and indirect connections with the sympathetic outflow and there is now considerable evidence that tonic activation of the PVN sympathetic pathway contributes to the sustained increased level of RSNA that occurs in conditions such as heart failure and neurogenic hypertension. The tonic activity of PVN sympathetic neurons, in turn, depends upon the balance of excitatory and inhibitory inputs. A number of neurotransmitters and neuromodulators are involved in these tonic excitatory and inhibitory effects, including glutamate, GABA, angiotensin II and nitric oxide. 3. The dorsomedial hypothalamic nucleus (DMH) also exerts a powerful influence over sympathetic activity, including RSNA, via synapses with sympathetic nuclei in the medulla and, possibly, also other brainstem regions. The DMH sympathetic pathway is an important component of the phasic sympathoexcitatory responses associated with acute stress, but there is no evidence that it is an important component of the central pathways that produce long-term changes in arterial pressure. Nevertheless, it is possible that repeated episodic activation of this pathway could lead to vascular hypertrophy and, thus, sustained changes in vascular resistance and arterial pressure. 4. Recent studies have reactivated the old debate concerning the possible role of the baroreceptor reflex in the long-term regulation of sympathetic activity. Therefore, central resetting of the baroreceptor-sympathetic reflex may be an important component of the mechanisms causing sustained changes in RSNA. However, little is known about the cellular mechanisms that could cause such resetting.
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PMID:Long-term regulation of arterial blood pressure by hypothalamic nuclei: some critical questions. 1585 52

A number of neurohumoral processes are activated in heart failure, including an increase in the plasma concentration of norepinephrine. Few studies have been performed to examine the role of the central nervous system in the activation of sympathetic outflow during heart failure (HF). In this paper I review these limited studies, with particular emphasis on examining the role of the paraventricular nucleus (PVN) in the exaggerated sympathetic outflow commonly observed in heart failure. The conclusion is that heart failure is associated with changes in specific areas in the brain and that alterations in the activation of neurons in the PVN are likely related to abnormalities in vasopressin production, blood volume regulation, and sympathoexcitation observed in the heart failure state. Furthermore, neuronal nitric oxide within the PVN that is involved in mediating sympathetic outflow via a GABA mechanism from the PVN may be deficient in inhibiting overall sympathetic outflow leading to the exaggerated sympathetic outflow commonly observed in heart failure.
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PMID:Role of paraventricular nucleus in mediating sympathetic outflow in heart failure. 1622 17

Sutherlandia frutescens (tribe Galegeae, Fabaceae), a popular plant in traditional medicine, is indigenous to South Africa, Lesotho, southern Namibia and southeastern Botswana. It is chemically, genetically and geographically extremely variable and has been divided into three subspecies and several regional forms. A second species, Sutherlandia tomentosa, is localized along the Cape coast. Sutherlandia is sometimes treated as part of the genus Lessertia. There are numerous vernacular names and a wide diversity of uses, including poor appetite, indigestion, stomach complaints, dysentery, colds, influenza, kidney conditions, fever, diabetes, internal cancers, uterine troubles, liver conditions, backache, rheumatoid arthritis, urinary tract infections, stress and anxiety, dropsy and heart failure. Notable is the use as a bitter tonic ("blood purifier"), anti-stress medication ('musa-pelo) and, at least since 1895, specifically as a cancer tonic (both as treatment and as prophylaxis). Externally it is applied to haemorrhoids, inflamed wounds and eye infections. Recent in vitro and in vivo studies have shown antiproliferative, anti-HIV, anti-diabetic, anti-inflammatory, analgesic, antibacterial, anti-stress, anticonvulsant and antithrombotic activities. Aqueous extracts often differ in activity from organic solvent extracts. The presence of high levels of free amino acids, non-protein amino acids such as canavanine and GABA, the cyclitol pinitol, flavonols and triterpenes (including SU1, a cycloartane-type triterpene saponin) provide plausible hypotheses on how these compounds, individually or collectively, may be responsible for the reputed efficacy in a wide range of ailments. Results of animal studies, as well as a phase I clinical study, have shown no indications of toxicity. Sufficient preclinical data are now available to justify controlled clinical studies.
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PMID:A review of the taxonomy, ethnobotany, chemistry and pharmacology of Sutherlandia frutescens (Fabaceae). 1876 Oct 68

1. Alterations in the paraventricular nucleus (PVN) are reported to be involved in sympathetic overactivity in chronic heart failure (CHF). Inhibitory inputs into the PVN contribute to sympathetic outflow. The aim of the present study was to comparatively determine the role of GABA mechanisms in the PVN in the tonic control of cardiovascular activity in anaesthetized sham and CHF rats. 2. The CHF model was induced by coronary artery ligation. Unilateral microinjection of the GABA(A) receptor agonist muscimol (0.1-0.8 nmol/200 nL) or the GABA(B) receptor agonist baclofen (0.25-2.0 nmol/200 nL) into the PVN produced similar, dose-dependent reductions in arterial pressure (AP), heart rate (HR) and renal sympathetic nerve activity (RSNA). This response was significantly blunted in CHF rats. In contrast, microinjection of the GABA(A) receptor antagonist bicuculline (25-200 pmol/200 nL) or the GABA(B) receptor antagonist CGP35348 (0.25-2.0 nmol/200 nL) into the PVN caused larger, dose-dependent increases in AP, HR and RSNA in sham than in CHF rats. 3. Polymerase chain reaction data showed that mRNA expression levels of the GABA(A) receptor alpha(1)-subunit and of the GABA(B1(a)) and GABA(B1(b)) receptor subtypes in the PVN were significantly lower in CHF than in sham rats. 4. The results of the present study suggest that the tonic inhibition mediated by both GABA(A) and GABA(B) receptors in the PVN on sympathetic outflow is blunted in CHF, which may be an important mechanism responsible for sympathetic hyperactivity in CHF.
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PMID:GABA(A) and GABA(B) receptor-mediated inhibition of sympathetic outflow in the paraventricular nucleus is blunted in chronic heart failure. 1967 34

Neuronal activity in the paraventricular nucleus (PVN) is known to be elevated in rats with heart failure. However, the type of neurons involved and the underlying synaptic mechanisms remain unknown. Here we examined spontaneous firing activity and synaptic currents in presympathetic PVN neurons in rats with myocardial infarction (MI), using slice patch clamp combined with the retrograde labeling technique. In PVN neurons projecting to the rostral ventrolateral medulla (PVN-RVLM), MI induced a significant increase in basal firing rate (1.79 to 3.02 Hz, P < 0.05) and a reduction in the frequency of spontaneous (P < 0.05) and miniature (P < 0.01) inhibitory postsynaptic currents (IPSCs). In addition, MI induced an increase in the paired-pulse ratio of evoked IPSCs (P < 0.05). Bicuculline, a GABA(A) receptor antagonist, increased the firing rate of PVN-RVLM neurons in sham-operated (1.21 to 2.74 Hz, P < 0.05) but not MI (P > 0.05) rats. In contrast, in PVN neurons projecting to the intermediolateral horn of the spinal cord (PVN-IML), MI did not induce any significant changes in the basal firing rate and the properties of spontaneous and miniature IPSCs. The properties of spontaneous excitatory postsynaptic currents (EPSCs) were not altered in either neuron group. In conclusion, our results indicate that MI induces an elevation of firing activity in PVN-RVLM but not in PVN-IML neurons and that the elevated firing rate is largely due to a decrease in GABA release. These results provide evidence for a novel target-selective synaptic plasticity in the PVN that is associated with the sympathetic hyperactivity commonly seen in heart failure.
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PMID:Reduction in synaptic GABA release contributes to target-selective elevation of PVN neuronal activity in rats with myocardial infarction. 2016


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